Update of Antiretroviral Agents in Adults and Adolescents 2008
STIs in Adolescents: An Update
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Transcript of STIs in Adolescents: An Update
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Do We Know How to Diagnose and Treat Pneumonia in
Children?B. Keith English, M.D.
Chair, Pediatrics and Human Development
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Pneumonia –
“The Captain of the Men of Death”– (William Osler)
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Case Presentation
• Previously healthy 13 yo athlete, began to complain of sore throat at football practice 9/1/09
• Fever and cough that evening; seen by PCP early 9/2/09: begun on oseltamivir and azithromycin
• Evening of 9/2/09: respiratory distress and chest pain
• Walked into Memphis ED at 10:30 pm; appeared ill but O2 sats reportedly 99% on room air
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Case Presentation
• Rapidly deteriorated in outside ED; required intubation and then had blood and copious frothy pink secretions suctioned from ETT
• Transported to Le Bonheur Children’s Hospital
• Treated with oseltamivir, vancomycin, azithromycin, meropenem
• Required oscillating ventilator, then ECMO; died four days later
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Diagnosis
• Rapid antigen test on admission positive for influenza A; confirmed as the 2009 novel H1N1 influenza A virus by PCR
• Admission blood and tracheal aspirate cultures yielded methicillin-resistant Staphylococcus aureus (MRSA)
• Necrotizing, hemorrhagic pneumonia at autopsy
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Influenza Epidemics2006-2009 (4/11/09)
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In March 2009, something unusual was occuring in Mexico
VeracruzVeracruz
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Novel H1N1 Virus Identified in Two Children in U.S. 4/15/09-4/17/09
In late March, 2009, two children in California had viral Cx that grew influenza A that could not be typed with standard reagents
April 15-17, 2009, CDC received the two isolates and identified a novel H1N1 swine-origin influenza A virus --similar viruses quickly identified from patients from the Mexico outbreak
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Emergence of a pandemic S-OIV strain
Segments
1 PB22 PB13 PA4 HA5 NP6 NA7 M8 NS
Human
N.A. Avian “Classic” orEurasian Swine
“Triple reassortant” Swine-origin influenza virus (S-OIV)
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Influenza Epidemics and a Pandemic: 2006-2009 (8/13/09)
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Influenza Epidemics and a Pandemic: 2006-2009 (10/24/09)
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346 patients admitted (210 between 8/25/09 and 10/25/09)
50 admissions to PICU; 5 deaths (4/5 with definite or probable secondary bacterial pneumonia)
Admissions to Le Bonheur Children’s Hospital with confirmed Novel H1N1 influenza: August 2009 – April 2010
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Pneumonia in Children
1. Leading cause of death in children less than 5 years of age: estimated 1.6 million deaths each year (98% in the developing world)* -- more than AIDS, malaria and measles combined *(Dagan et al, “The Remaining Challenge of Pneumonia, PIDJ 30: 1-2, 2011)
2. More than 11 million children hospitalized with pneumonia worldwide each year
3. We should know more about it than any other infection ….. but ….
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What we DON’T know about pneumonia in children
1. Which children with a clinical diagnosis of bacterial pneumonia actually have bacterial infection?
2. How common is “co-infection” or “secondary infection” in children with pneumonia -- and does this matter?
3. What is the best antibiotic treatment for children (or adults) with bacterial pneumonia caused by specific pathogens? (e.g., Streptococcus pneumoniae)
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What we DON’T know about pneumonia in children
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Bacterial Pneumonia in Children
• Bacterial pneumonia long presumed to be distinct from viral or “atypical” pneumonia (mycoplasmal, chlamydial) on clinical and radiological grounds
• However, there is considerable overlap; expert radiologists disagree with each other (and with the microbiology results!)
• Recent studies using more sensitive techniques document frequent co-infection (especially viral and bacterial co-infection)
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Bacterial Causes of Pneumonia in Children
• Lung puncture studies from 60s and 70s identified Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus as causes of severe bacterial pneumonia in children in the developing world
• Group A streptococcus and enteric gram-negative bacteria also implicated
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Etiology of Pneumonia in Children Often Unknown
• Difficult to identify the specific etiology of presumed bacterial pneumonia in children
• -- Collection of sputum samples unreliable
• -- Blood cultures usually negative
• -- Thoracentesis may not be diagnostic after antibiotic therapy
• Only a minority of cases “confirmed” (e.g., positive blood or pleural fluid Cx or PCR)
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What we DON’T know about pneumonia in children
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Bacterial Pathogens in Pediatric Pneumonia: Dallas (2000)
48 of 154 children (31%) hospitalized with Dx of pneumonia had a single bacterial pathogen identified* (Michelow et al, Pediatrics, 113: 701, 2004)
– Streptococcus pneumoniae 73% (35/48)
– Mycoplasma pneumoniae 23% (11/48)
– Chlamydia pneumoniae 13% (6/48)
– Mycobacterium tuberculosis 2% (1/48)
(* overall 60% of patients had a bacterial pathogen identified while 45% had documented viral infection)
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Co-Pathogens in Pediatric Pneumonia: Dallas
Michelow et al, Pediatrics 113: 701, 2004.
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Etiology of Pneumonia in Hospitalized Children
o DALLAS
– 154 pts (6 wks -18yrs)
– 60% with documented bacterial infection
– 45% with documented viral infection:
Pneumococcus 44%
Mycoplasma 14%
Chlamydia 9%(Michelow et al, Pediatrics, 113: 701,
2004)
o ATHENS
– 75 pts (5-14 yrs)
– 40% with documented bacterial infection
– 65% with documented viral infection)
o Mycoplasma 35%
Pneumococcus 7%
Chlamydia 3%(Tsolia, et al, Clin Infect Dis 39: 681, 2004)
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CDC EPIC Study
“Etiology of Pneumonia in the Community (EPIC)” study funded by the CDC (2009-2012)
Memphis was 1 of 4 national sites for this study – enrolling pediatric patients only (other sites: Vanderbilt, Northwestern, Salt Lake City)
Jain et al NEJM 372: 835, 2015
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CDC EPIC Study Aims
Main purposes were to determine:
1. Incidence of hospitalized pneumonia
2.Etiology of pneumonia in hospitalized patients: by evaluating blood, sputum and nasal/throat swabs for respiratory viruses, typical and atypical bacteria --using culture, molecular diagnostics and serology
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CDC EPIC Study– Le Bonheur Arm
Study personnel enrolled patients approximately 18 hours/day, 7 days/wk
Le Bonheur enrolled 988 pts in 30 months (most of any site)
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CDC EPIC Study
Huge cohort of patients with clinical and radiologic evidence of pneumonia
Testing algorithm likely much more sensitive than any published experience re: identification of viral pathogens
BUT it remains uncertain whether these tests can/will detect most cases of bacterial pneumonia
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Etiology of Pneumonia in Children: Le Bonheur Cohort (n=742)
Etiology Number
Typical bacterial 5
Typical bacterial-viral coinfection 26
Atypical bacterial 19
Atypical bacteria-viral coinfection 17
Viral 553
Total number of subjects with etiology identified
620 (84% of cohort)
Arnold et al, IDSA, October, 2012
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CDC EPIC Study: Results Most children hospitalized and treated for
pneumonia have viral pneumonia
Less than 10% have documented bacterial pneumonia (pyogenic bacteria plus mycoplasma)
Question remains – what percent of hospitalized children with viral pneumonia have bacterial co-infection that we are unable to document?
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What we DON’T know about pneumonia in children
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Impact of Beta-Lactam Resistance on Outcome of Bacterial Pneumonia?
• High rates of resistance to penicillins/cephalosporins in Streptococcus pneumoniae -– rare failures
• Community-acquired pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA) – universal failures*
*(ceftaroline clinical trials underway in children)
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Cephalosporin Treatment Failures in Pneumococcal Meningitis
Bradley et al - Reported first case of extended spectrum cephalosporin failure in meningitis caused by multi-resistant S. pneumoniae (Pediatr Infect Dis J, 1991;10:871).
Sloas et al - Reported 3 cases of cephalosporin treatment failure in penicillin and cephalosporin resistant S. pneumoniae meningitis in Memphis (cefotaxime MICs 8-32 g/ml) (Pediatr Infect Dis J, 1992;11:662).
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Impact of Antibiotic Resistance on Rx of Other Invasive Pneumococcal Infections
Most patients without meningitis will respond to therapy with intravenous beta-lactams, especially if the isolate’s MIC is < 2 g/ml.
Two treatment failure with bone/joint infection due to highly-resistant pneumococci in Memphis (Abbasi et al, PIDJ, 15: 78, 1996)
Possible treatment failures in pneumonia, especially if MIC > 4 g/ml
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Beta-Lactams *Usually Adequate Therapy for Pneumonia due to “Non-Susceptible” Pneumococci Barcelona study (Adults): “R” to Pen or Ceph: no effect on
outcome (Pallares, et al, N Engl J Med 333: 474, 1995)
Two large pediatric studies: No increased morbidity or mortality assc with “R” strains
• (A) PMPSSG Study (U.S.) Tan, et al, Pediatrics 102: 1369, 1998
• (B) South American Study Deeks, et al, Pediatr 103: 409, 1999
International Multicenter study (prospective) in adults “R” to Pen/Ceftx/Cefotax: discordant Rx had no effect on outcome (but R to cefuroxime assc with Rx failure) Yu, et al, Clin Infect Dis 37: 230, 2003.
*However, these studies included few infections caused by pneumococci with with Pen/Ceph MICs ≥ 4 g/ml
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Beta-Lactam Failures in Rx of pneumococcal pneumonia?
Buckingham et al reported breakthrough bacteremia and meningitis in an 18 mo old treated for pneumonia with cefotaxime/cefuroxime (MICs 2/8 g/ml)
(J Pediatr 132: 174, 1998)
Dowell et al reported cefuroxime failure in 18 mo old with pneumonia (MIC 8 g/ml) (Clin Infect Dis 29:462, 1999)
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Beta-Lactam Failures in Rx of pneumococcal pneumonia? II
“Mortality from Invasive Pneumococcal Pneumonia in the Era of Antibiotic Resistance, 1995-1997”
(Feikin, et al, Amer J Public Health 90: 223-9, 2000)
CDC multi-state surveillance project: 5837 cases of pneumococcal pneumonia (98% + BCx, 2% + pl. fluid)
93% of cases were in adults
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Beta-Lactam Failures in Rx of pneumococcal pneumonia?
CDC surveillance 95-97
• Case Fatality Rate 12.6% adults; 2.4% children
• Overall mortality not related to Penicillin or Cefotaxime MIC (OR 2.3/1.3)
However, Deaths occurring after 4th hospital day strongly associated with Pen/Cef resistance:
Pen MIC > 4 g/ml: OR 7.1 (95% CI 1.7-30.0)
Cef MIC > 2 g/ml: OR 5.9 (95% CI 1.1-33.0)
But treatment information not available (effect of discordant Rx not examined)
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EFFECT OF PENICILLIN ON SURVIVAL IN PATIENTS WITH BACTEREMIC PNEUMOCOCCAL
PNEUMONIA
(Austrian and Gold, Ann Intern Med, 60:759, 1964)
PENICILLIN ( 298 )
SERUM ( 93 )
UNTREATED ( 384 )
DAY OF ILLNESS
%
SU
RV
IVO
RS
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Treatment “failures” with beta-lactams are rare
BUT documented failures may be rare because very few infections are caused by isolates with Pen MIC > 8 g/ml (<1%)
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Is the Focus on Antibiotic Resistance Missing the Point?
Beta-lactams (and other cell-wall active agents) may not be optimal therapy for severe infections caused by susceptible bacteria
Therapy with alternative agents (alone, or in combination with beta-lactams) that trigger less rapid bacterial lysis and less inflammation may be superior (clear consensus for group A strep necrotizing fasciitis – “Eagle Effect”; strong evidence in experimental pneumococcal meningitis)
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Combination Therapy for Severe Pneumococcal Pneumonia ?
Baddour et al reported markedly reduced mortality (23.4 vs. 55.3%) in critically ill adults with bacteremic pneumococcal pneumonia who received combination antibiotic therapy (usually macrolide + beta-lactam) vs beta-lactam alone)(prospective) (Am J Resp Crit Care Med 2004; 15: 440)
Martinez et al reported comparable benefit in adults with pneumococcal pneumonia in two large retrospective studies -- in the 2nd study, benefit was also noted in all patients with CAP
(Clin Infect Dis 2003; 15:396; Eur J Clin Microbiol Infect Dis 2005; 24: 190)
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Why Might Combination Therapy Be Superior?
1. Not likely to be synergistic killing based on in vitro or animal model data
2. Anti-inflammatory effects of macrolides ?
3. Indirect effects on host response because of reduced/delayed bacterial lysis?
4. Modulation of bacterial virulence factor expression?
5. Effect on co-pathogens? (unlikely)
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Combination Therapy for Severe Pediatric Pneumonia?
Much lower mortality rate in children with pneumococcal pneumonia
Macrolide frequently part of empiric therapy for older children (to cover mycoplasma/chlamydia)
High rates of macrolide resistance in pneumococci causing pediatric infections make these drugs poor options for monotherapy
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Predominant Role of Bacterial Pneumonia as a Cause of Death in Pandemic Influenza: Implications for Pandemic Influenza Preparedness
David M. Morens, Jeffery K. Taubenberger, and Anthony S. Fauci
National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland
Journal of Infectious Diseases 2008; 198:962–70
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“If grippe condemns, the secondary infections execute”
Louis Cruveilhier, 1919
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Influenza-Pneumococcus Synergy In Mice
McCullers, J Infect Dis 190: 519, 2004
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Days 1 3 5 7 8 2 4 6 0
# Mice withPneumonia /
Total
8/8
# Mice Dead /Mice with Pneumonia
8/8
Influenza-Pneumococcus Synergy:Mice Treated with Ampicillin Alone Die
Mouse #1
2
3
4
5
McCullers, J Infect Dis 190: 519, 2004
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Azithromycin superior to ampicillin in mouse model of
post-influenzal pneumococcal pneumonia
-
p < 0.05 by log rank test compared to all other groups
Karlström, Boyd, English and McCullers, J Infect Dis 2009;199:311.
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Macrolides as Adjunctive Rx of Pneumonia?
• Is the effect non-specific (as seen in cystic fibrosis, in Asian patients with panbronchiolitis) or specific – e.g, would it be seen on Azithromycin-Resistant bacteria?
• (40-50% of pneumococci isolated at Le Bonheur are macrolide-resistant)
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Kar
Karlstrom et al, Infect Dis. 2011, 204:1358-66
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2011 PIDS/IDSA Pneumonia Guidelines
Clinical Infectious Diseases 2011; 53: 617-630.
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2011 PIDS/IDSA Pneumonia Guidelines: Outpatients
Amoxicillin still best outpatient agent (90 mg/kg/day recommended)
Amoxicillin-clavulanate alternative
Clindamycin or levofloxacin or linezolid recommended for infections caused by highly-beta-lactam resistant pneumococci (PCN MIC >/= 4)
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2011 PIDS/IDSA Pneumonia Guidelines: Inpatients
IV ampicillin or ceftriaxone/cefotaxime best choice for most hospitalized children
Add clindamycin or vancomycin if Staph aureus suspected (e.g., severe or complicated pneumonia)
Role of combination therapy uncertain – possible benefit in severe cases
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Duration of Therapy for Complicated Pneumonia?
10 days of therapy recommended for uncomplicated pneumonia
Shorter courses likely effective in mild disease; longer treatment “may be required” for infections caused by MRSA, etc (weak evidence)
Longer courses – 2-4 weeks – recommended for patients with pneumonia complicated by parapneumonic effusion/empyema (weak evidence)
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Route of Therapy for Complicated Pneumonia?
Oral vs IV choice –
– Depends on …
– Patient factors (age, home situation, availability of followup),
– The pathogen (e.g., Staph vs pneumococcus)
– Susceptibility results (e.g., clindamycin, linezolid. or levofloxacin highly bioavailable given by mouth)
No “one size fits all” recommendation
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Prevention of Pneumonia I
Vaccines directed at influenza (and, eventually, other respiratory viruses) and pneumococcus can prevent many cases of pneumonia in children
Efforts to develop a Staph vaccine remain problematic; a promising group A strep vaccine is in clinical trials
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Prevention of Pneumonia II
• First generation conjugated pneumococcal vaccine (PCV7) associated with 25-30% reduction in all pneumonia (CXR-confirmed, per WHO criteria (Hansen et al, PIDJ 25: 779, Sept, 2006)
• However, 44% of complicated pneumonias in one large U.S. study* were caused by pneumococcal serotypes not in PCV7
*Tan et al, Pediatrics, 2002: 110: 1-6.
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Prevention of Pneumonia III
• PCV13 includes serotypes 1 and 3 and more than 80% of the serotypes causing complicated pneumonia in the U.S.
• Synergy between influenza vaccine and pneumococcal vaccine in preventing pneumonia